Workshop on Neurogenesis and Aging National Institute on Aging March 16-17, 2020 Final May 27, 2020 This meeting summary was prepared by Bethany Stokes, Rose Li and Associates, Inc., under contract to Sigma Health Consulting and the National Institute on Aging. The views expressed in this document reflect individual opinions of the meeting participants and not necessarily those of Sigma Health Consulting or the National Institute on Aging. Review of earlier versions of this meeting summary by the following individuals is gratefully acknowledged: Maura Boldrini, Michael Bonaguidi, Dana Carluccio, Joseph Castellano, Amanda DiBattista, Ionut Dumitru, Rusty Gage, Shaoyu Ge, Rene Hen, Jenny Hsieh, Orly Lazarov, Mirjana Maletic-Savatic, Amar Sahay, Alejandro Schinder, Hongjun Song, Matt Sutterer, Kristyn Sylvia, Nancy Tuvesson, Saul Villeda, Molly Wagster, Ashley Webb, Brad Wise. Neurogenesis and Aging March 16-17, 2020 Table of Contents Executive Summary ............................................................................................................... 1 Meeting Summary ................................................................................................................. 3 Introduction to Mammalian Adult Neurogenesis ............................................................................3 Session I: Neurogenesis in the Adult Human Brain ..........................................................................4 Adult Hippocampal Neurogenesis and Aging in Health and Disease ................................................... 4 The Role of Hippocampal Neurogenesis in Aging-Linked Cognitive Deficits and Alzheimer’s Disease .............................................................................................................................. 6 Neurogenesis in the Postnatal and Adult Human Brain ....................................................................... 7 Solving Human Neurogenesis in Vivo: Toward Better Understanding and Therapy of Brain Disorders ..................................................................................................................................... 9 Discussion of Session I ........................................................................................................................ 10 Session II: Regulation of Neurogenesis in the Aging Brain .............................................................. 12 Regulation of Neurogenesis in Aging and Disease ............................................................................. 12 Enhanced Plasticity of New Neurons in the Aging Hippocampus ...................................................... 13 Embryonic Origin and Maintenance of Adult Neural Stem Cells ....................................................... 15 Blood-borne Regulators of the Hippocampal Neurogenic Niche ....................................................... 16 Transcriptional and Epigenetic Regulation of Neural Stem Cell Quiescence and Activation ............. 18 Adult Neurogenesis and the Neurobiology of Individuality ............................................................... 19 Discussion of Session II ....................................................................................................................... 21 Session III: Functional Significance of Adult Neurogenesis ............................................................. 22 The Function of New Neurons in Adult and Aging Hippocampal Neural Circuits .............................. 22 Blood: At the Interface of Aging and Adult Neurogenesis ................................................................. 23 Pathological Roles and Mechanisms of Aberrant Neurogenesis in Epilepsy ..................................... 25 Rejuvenating, Re-Engineering, and Restoring Aging Memory Circuits .............................................. 26 Targeting Hippocampal Neurogenesis to Improve Pattern Separation in Aging ............................... 28 Discussion of Session III ...................................................................................................................... 29 Final Discussion: Gaps and Opportunities ..................................................................................... 31 Appendix 1: Agenda ............................................................................................................ 33 Appendix 2: Speakers and Attendees ................................................................................... 36 Table of Contents Page ii Neurogenesis and Aging March 16-17, 2020 Acronym Definitions 1HMRS proton magnetic resonance imaging ABLIM3 actin-binding LIM protein 3 AD Alzheimer’s disease ATAC-Seq assay for transposase-accessible chromatin using sequencing β2M beta 2 microglobulin BDNF brain-derived neurotrophic factor BDZ benzodiazepine C14 carbon 14 CA1 cornu ammonis 1 CA3 cornu ammonis 3 CCL11 C-C Motif Chemokine Ligand 11 Cis-MUFA cis-monounsaturated fatty acid CNS central nervous system CyPA cyclophilin A DCX doublecortin DG dentate gyrus DTI diffusion tensor imaging EE environmental enrichment EGF epidermal growth factor FAD familial Alzheimer’s disease FFI feed-forward inhibition GABA gamma aminobutyric acid GCV ganciclovir Gpdl1 glycosylphosphatidylinositol-specific phospholipase D1 GPCR G protein-coupled receptor Hopx homeobox-only protein homeobox HSC hemopoietic stem cells HNF4α hepatocyte nuclear factor 4 alpha IGF-1 insulin-like growth factor 1 KO knockout KI knock-in Klf9 kruppel-like factor 9 LEC lateral entorhinal cortex LRIG-1 Leucine-rich repeats and immunoglobulin-like domains protein 1 LTP long-term potentiation MADRS Montgomery-Asberg Depression Rating Scale MEA multi-electrode array MCI mild cognitive impairment MDD major depressive disorder MEC medial entorhinal cortex Mfge8 milk fat globule-EGF factor 8 protein Acronym Definitions Page iii Neurogenesis and Aging March 16-17, 2020 MS mass spectrometry MRI magnetic resonance imaging MRS magnetic resonance spectroscopy NIA National Institute on Aging NMDA N-methyl-D-aspartate NOR novel object recognition NSC neural stem cell OF open field PI3K phosphatidylinositol-3 kinase Prox1 Prospero-related homeobox 1 PSA-NCAM polysialylated-neural cell adhesion molecule qPCR quantitative polymerase chain reaction RNA-Seq RNA sequencing S1P sphingosine-1-phosphate Sox2 SRY (sex determining region Y)-box 2 SSRI serotonin reuptake inhibitor SST somastatin SVD singular value decomposition SVZ subventricular zone TIMP2 TIMP metallopeptidase inhibitor 2 TrkB tropomyosin receptor kinase B VEGFR2 vascular endothelial growth factor receptor 2 Acronym Definitions Page iv Neurogenesis and Aging March 16-17, 2020 Executive Summary The National Institute on Aging (NIA) held a virtual workshop on March 16-17, 2020, on Neurogenesis and Aging. Neurogenesis may contribute to many critical processes in the brain, such as memory formation, learning, and pattern separation, and this process is compromised during aging. Although many studies have assessed the impact of neurogenesis on aging and vice versa, the underlying mechanisms remain poorly understood. The goal of this workshop was to review current findings, discuss knowledge and research gaps, and identify priorities for future research in neurogenesis and aging. The workshop was organized into three sessions: (1) neurogenesis in the adult human brain, (2) regulation of neurogenesis in the aging brain, and (3) functional significance of adult neurogenesis. A concluding discussion was also held to express final thoughts and identify addressable gaps and opportunities in the field. The study of neurogenesis during aging and age-related neurodegenerative diseases requires characterization of the many cell types and factors involved. Because increased neurogenesis can be harmful under some conditions (e.g., epilepsy), further investigation is necessary to understand (1) the precise level of neurogenesis that provides benefits during normal physiological conditions, aging, and in brain diseases (e.g., Alzheimer’s disease [AD]) and (2) whether the level of neurogenesis can be regulated through behavior or physiological intervention. Accurate characterization of neurogenesis in mouse models, non-human primates, and humans is essential to better understand the mechanisms underlying neurogenesis. Moreover, visualization of real-time neurogenesis processes is needed to move the field forward. Behavioral, genetic, and molecular interventions to regulate neurogenesis were discussed as strategies to improve cognitive outcomes during aging and in AD. Further assessment of how these interventions will translate to humans is required for wide-scale implementation. Each session concluded with the identification of scientific gaps and opportunities to improve neurogenesis and aging research; two distinct topic areas emerged and are summarized below. Mechanisms of Neurogenesis • Impact of dysfunctional new neurons on the hippocampal circuit in aging and AD. • Collective evaluation of the neurogenic niche (i.e., rather than separately assessing individual parts). • Characterization of the neural stem cell niche in aging and AD (e.g., vascular, microglial, astrocytic, or peripheral factors). • Identification of differences in neurogenesis between humans and model organisms. • Exploration of both positive and potentially negative functional outcomes of newly integrated neurons in aging hippocampal circuits and in models of AD. • Ideal balance of neurogenesis and mature neuron maintenance in aging and AD. Executive Summary